Citation and License

Arthritis Research & Therapy 2005, 7:R694-R703
doi:10.1186/ar1727

Published: 1 April 2005

Abstract

Leflunomide, a potent disease-modifying antirheumatic drug used in the treatment of
rheumatoid arthritis (RA), exhibits anti-inflammatory, antiproliferative and immunosuppressive
effects. Although most of the beneficial effects of leflunomide have been attributed
to its antimetabolite activity, mainly in T cells, other targets accounting for its
potency might still exist. Because of mounting evidence for a prominent role of dendritic
cells (DCs) in the initiation and maintenance of the immune response in RA, we analyzed
the effect of the active metabolite of leflunomide (A77 1726; LEF-M) on phenotype
and function of human myleloid DCs at several stages in their life cycle. Importantly,
DCs differentiated in the presence of LEF-M exhibited an altered phenotype, with largely
reduced surface expression of the critical co-stimulatory molecules CD40 and CD80.
Furthermore, treatment of DCs during the differentiation or maturation phase with
LEF-M aborted successful DC maturation. Exogenous addition of uridine revealed that
DC modulation by LEF-M was independent of its proposed ability as an antimetabolite.
In addition, the ability of DCs to initiate T-cell proliferation and to produce the
proinflammatory cytokines IL-12 and tumour necrosis factor-α was markedly impaired
by LEF-M treatment. As a molecular mechanism, transactivation of nuclear factor-κB,
an transcription factor essential for proper DC function, was completely suppressed
in DCs treated with LEF-M. These data indicate that interference with several aspects
of DC function could significantly contribute to the beneficial effects of leflunomide
in inflammatory diseases, including RA.